AZD8797 (KAND567) is an allosteric non-competitive and orally active antagonist of the human CX3CR1 receptor; antagonizes CX3CR1 and CXCR2 with K i s of 3.9 and 2800 nM, respectively.
In Vitro
In a flow adhesion assay, AZD8797 antagonizes the natural ligand, fractalkine (CX3CL1), in both human whole blood (hWB) and in a B-lymphocyte cell line with IC 50 values of 300 and 6 nM respectively. AZD8797 also prevents G-protein activation in a [ 35 S]GTPγS accumulation assay. AZD8797 positively modulates the CX3CL1 response at sub-micromolar concentrations in a β-arrestin recruitment assay. In equilibrium saturation binding experiments, AZD8797 reduces the maximal binding of 125I-CX3CL1 without affecting K d. AZD8797 binds selectively with high affinity to human and rat CX3CR1 (K i of hCX3CR1, 4 nM; K i of rCX3CR1, 7 nM, respectively). The equilibrium dissociation constant, K B , demonstrates that AZD8797 is a very potent inhibitor for human CX3CR1 (10 nM). The potency is threefold lower for rat CX3CR1 (29 nM) and decreases even further at mouse CX3CR1 (54 nM). MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
AZD8797 treatment in Dark Agouti rats with myelin oligodendrocyte glycoprotein-induced EAE results in reduced paralysis, CNS pathology, and incidence of relapses. The compound is effective when starting treatment before onset, as well as after the acute phase. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Animal administration
Rats: AZD8797 is formulated in 30–35% (wt/wt) hydroxy-propyl-beta-cyklodextrin and administered s.c. through osmotic minipumps. Treatment is blinded to the operator. The plasma concentration of AZD8797 is analyzed twice from each rat . aladdin has not independently confirmed the accuracy of these methods. They are for reference only.
